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1.
Artigo em Inglês | MEDLINE | ID: mdl-31701626

RESUMO

OBJECTIVE: To investigate the role of driver mechanism and the effect of electrogram dispersion guided driver mapping and ablation in atrial fibrillation (AF) at different stages of progression. METHODS: 256 consecutive AF patients who had undergone PVI plus driver ablation or conventional ablation were divided into 3 groups: paroxysmal AF (PAF, Group A, n=51), persistent AF (PsAF) (Group B, n=38); and long-standing persistent AF(LS-PsAF) (Group C, n=39). PVI was performed with guidance of ablation index. The electrogram dispersion was analyzed for driver mapping. RESULTS: The most prominent driver regions were at roof (28.0%), posterior wall (17.6%) and bottom (21.3%). From patients with paroxysmal AF to those with persistent and long-standing persistent AF: the complexity of extra-PV drivers including distribution, mean number and area of dispersion region increased (P<0.001). Patients who underwent driver ablation vs. conventional ablation had higher procedural AF termination rate (76.6% vs 28.1%, P<0.001). With AF progression, the termination rate gradually decreased from group A to C, and the role of PVI in AF termination was also gradually weakened from group A to C (39.6%, 7.4% and 4.3%, P<0.001) in patients with driver ablation. At the end of the follow-up, the rate of SR maintenance was higher in patients with driver ablation than those with conventional ablation (89.1% vs 70.3%, P<0.001). CONCLUSION: The formation of extra-PV drivers provides an important mechanism for AF maintenance with their complexity increasing with AF progression. Electrogram dispersion guided driver ablation appears to be an efficient adjunctive approach to PVI for AF treatment. This article is protected by copyright. All rights reserved.

2.
Cardiology ; 142(3): 158-166, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31189165

RESUMO

AIM: During cardiac resynchronization therapy (CRT), optimized programming of the atrioventricular (AV) delay and ventricular-to-ventricular (VV) interval can lead to improved hemodynamics, symptomatic response, and left ventricular systolic function. Currently, however, there is no recommendation for the best optimization method. This study aimed to compare the long-term clinical outcomes of 4 different CRT optimization methods. METHODS: One hundred and twenty-four consecutive CRT patients with severe heart failure and left bundle-branch block configuration were randomly assigned into four groups to undergo AV/VV delay optimization through echocardiogram (ECHO; n = 30), electrocardiogram (ECG; n = 32), QuickOpt algorithm (n = 28), and nominal AV/VV (n = 36) groups. Patients were followed up and underwent examinations, including New York Heart Association (NYHA) cardiac functional classification, 6-min walking distance (6MWD), and echocardiography, at 6, 12, 24, 36, and 48 months, respectively. The patients' survival and clinical outcomes were compared among the four groups. RESULTS: Kaplan-Meier survival analyses showed that the median survival was the same in the 4 groups: ECHO, 43 months; ECG, 44 months; QuickOpt, 44 months, and nominal, 41 months. At the 6-month follow-up, the reduction in left ventricular end diastolic diameter (LVEDD) was significantly less in the nominal group (-1.91 ± 2.58 mm) than that in the other three groups (ECHO: -3.70 ± 2.78 mm, p = 0.012; ECG: -3.53 ± 3.14 mm, p = 0.020; QuickOpt: -3.46 ± 2.65 mm, p = 0.032); 6MWD was significantly shorter in the nominal group (87.88 ± 34.76 m) than that in the other three groups (ECHO: 120.63 ± 56.93 m, p = 0.006; ECG: 114.97 ± 54.95 m, p = 0.020; QuickOpt: 114.57 ± 35.41 m, p = 0.027). Left ventricular ejection fraction (LVEF) significantly increased in ECHO (7.23 ± 2.76%, p = 0.010), ECG (8.50 ± 3.17%, p < 0.001), and QuickOpt (8.39 ± 2.90%, p < 0.001) compared with the nominal group (5.35 ± 2.59%). There were no significant differences among the groups in the aforementioned parameters at 24, 36, and 48 months, respectively. CONCLUSION: While LVEDD, LVEF, 6MWD, and NYHA were significantly improved in ECHO, ECG, and QuickOpt at 6 months, there were no significant improvements in any of the groups at 12, 24, and 48 months. These findings suggested that the long-term effect of the four CRT methods for heart failure was not significantly different.

3.
Clin Lab ; 64(6): 915-921, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29945308

RESUMO

BACKGROUND: Breast cancer is the second leading cause of cancer-related death among women worldwide. The aim of this study is to investigate the role of miR-142-3p in breast cancer cells and the related mechanism. METHODS: Sixty paired breast cancer tissues were collected and 60 breast tissues from patients with mammary hyperplasia served as the control group. The expression of miR-142-3p was examined using RT-qPCR methods; moreover, we also performed receiver operating characteristic (ROC) curve analysis to determine whether miR142-3p can distinguish breast cancer patients from the controls. Next, HMGA1 and FZD7 have been predicted as target genes of miR-142-3p, and the expressions of HMGA1 and FZD7 in breast cancer tissue and the control group were examined using RT-qPCR and western blot methods. RESULTS: miR-142-3p was significantly down-regulated in breast cancer tissue compared with the controls, and the levels of miR-142-3p was negatively correlated with the tumor size, degree of differentiation, and metastasis (p < 0.01). Moreover, results of ROC curve analysis indicated that the expression of miR-142-3p can distinguish between patients with breast cancer and the control group (AUC = 0.819, 95% CI, 0.756 - 0.881). Furthermore, the expressions of HMGA1 and FZD7 were significantly up-regulated in patients with breast cancer compared with the controls. The level of miR-142-3p was negatively correlated with expressions of HMGA1 (r = -0.3507, p = 0.006) and FZD7 (r = -0.3410, p = 0.0077) in patients with breast cancer. CONCLUSIONS: Our results proved that miR-142-3p may serve as a tumor suppressor in breast cancer by suppressing the expression of oncogene HMGA1 and FZD7, suggesting that miR-142-3p has the potential to become a diagnostic marker and therapeutic target for the early diagnosis and treatment of breast cancer.

4.
Pacing Clin Electrophysiol ; 41(2): 172-178, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29023875

RESUMO

BACKGROUND: In longstanding persistent atrial fibrillation (LPeAF), the ideal endpoint of ablation remains to be determined. This study was to explore the value of pursuing AF termination or no with the same strategy during ablation on the long-term outcomes in patients with LPeAF. METHODS: Utilized "CCL" strategy is a fixed ablation approach consisting of circumferential pulmonary vein antrum isolation, ablation of complex fractionated atrial electrogram, and linear ablation between two anatomical structures (the mitral isthmus, left atrial roof). Note that 400 patients were randomized to group A (technical endpoint) and group B (pursuing AF termination). RESULTS: A group with technical endpoint had lower rate of acute AF termination (AF→sinus rhythm, 3.5% vs 18.1%; AF→atrial tachycardia, 23.7% vs 44.7%; P < 0.01) and shorter duration of ablation (164.9 ± 20.8 vs 223.4 ± 24.9, P < 0.01), radiofrequency delivery time (69.8 ± 18.1 vs 102.2 ± 26.3, P < 0.01), and x-ray exposure time (18.2 ± 8.8 vs 27.9 ± 12.4, P < 0.01) than those in B group (pursuing AF termination). During follow-up, freedom from atrial arrhythmias did not differ between the two groups after a single ablation procedure (46.5% vs 54.3%, P=0.12) and the final ablation procedure (60.1% vs 65.8%, P  =  0.24). CONCLUSION: In patients of LPeAF, pursuing AF termination during ablation was associated with similar long-term clinical outcome compared to that with technical endpoint. Ablation to termination is not the best strategy during ablation.

5.
Clin Chem Lab Med ; 56(3): 502-511, 2018 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28902616

RESUMO

BACKGROUND: The MADS-box transcription factor myocyte enhancer factor 2C (MEF2C) is required for the cardiac development and postnatal adaptation and in mice-targeted disruption of the MEF2C gene results in dilated cardiomyopathy (DCM). However, in humans, the association of MEF2C variation with DCM remains to be investigated. METHODS: The coding regions and splicing boundaries of the MEF2C gene were sequenced in 172 unrelated patients with idiopathic DCM. The available close relatives of the index patient harboring an identified MEF2C mutation and 300 unrelated, ethnically matched healthy individuals used as controls were genotyped for MEF2C. The functional effect of the mutant MEF2C protein was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. RESULTS: A novel heterozygous MEF2C mutation, p.Y157X, was detected in an index patient with adult-onset DCM. Genetic screen of the mutation carrier's family members revealed that the mutation co-segregated with DCM, which was transmitted as an autosomal dominant trait with complete penetrance. The non-sense mutation was absent in 300 control individuals. Functional analyses unveiled that the mutant MEF2C protein had no transcriptional activity. Furthermore, the mutation abolished the synergistic transactivation between MEF2C and GATA4 as well as HAND1, two other transcription factors that have been associated with DCM. CONCLUSIONS: This study indicates MEF2C as a new gene responsible for human DCM, which provides novel insight into the mechanism underpinning DCM, suggesting potential implications for development of innovative prophylactic and therapeutic strategies for DCM, the most prevalent form of primary myocardial disease.


Assuntos
Cardiomiopatia Dilatada/genética , Adulto , Cardiomiopatia Dilatada/metabolismo , Feminino , Células HeLa , Humanos , Fatores de Transcrição MEF2/deficiência , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Células Tumorais Cultivadas
6.
Int J Cardiol ; 228: 853-860, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27888765

RESUMO

BACKGROUND: The electrophysiological characteristics of patients without recurrence after ablation of persistent atrial fibrillation (AF) have not been systematically determined. This study compared the electrophysiological characteristics in patients with and without recurrence of AF after persistent AF ablation. METHODS: Forty-five patients without recurrence of AF after persistent AF ablation were enrolled to assess electrophysiological characteristics including pulmonary vein (PV) reconnection, the mitral isthmus (MI) line and the roof line reconduction. Ninety-five patients with recurrence of AF after ablation were used as the control group. RESULTS: Among patients without recurrence, recovery of PV conduction was observed in 37 of 45 (82.2%) patients: 3/45 (6.7%) reconnection in 4 veins, 7/45 (15.6%) in 3 veins, 11/45 (24.4%) in 2 veins, and 16/45 (35.6%) in 1 vein. No significant differences were seen in the proportion of patients with PV reconnection compared to patients with recurrence (p>0.05). Among patients without recurrence, the MI line reconduction was observed in 3/45 (6.7%) patients; the roof line conduction was observed in 5/45 (11.1%) patients. In comparison, patients with clinical recurrence of AF had recovery of the MI line conduction in 27/95 (28.4%) and recovery of the roof line conduction in 26/95 (27.4%). Significant differences were seen between these two groups (6.7% vs 28.4%, p=0.004; 11.1% vs 27.4%, p=0.031). CONCLUSION: Although a high incidence of PV reconnection was similarly observed in patients with and without recurrence of AF, a lower incidence of lines reconduction was observed in patients without recurrence of AF.


Assuntos
Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/terapia , Ablação por Cateter , Idoso , Fibrilação Atrial/diagnóstico , Estudos de Casos e Controles , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Veias Pulmonares , Recidiva , Resultado do Tratamento
7.
JACC Clin Electrophysiol ; 3(9): 950-959, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29759719

RESUMO

OBJECTIVES: This study sought to determine if anatomic atrial ganglionated plexus (GP) ablation leads to long-term sinus rate (SR) increase and improves quality of life in patients with symptomatic sinus bradycardia (SB). BACKGROUND: Atrial GP ablation has been demonstrated to increase SR in our previous study. Atrial GP ablation may also be effective in treating patients with symptomatic SB. METHODS: Sixty-two patients with symptomatic SB were recruited: Group A included patients <50 years of age (n = 40); Group B included patients ≥50 years of age (n = 22). All patients underwent anatomic ablation of the main atrial GP, and 24-h Holter monitoring and quality-of-life assessment were performed during 1 year of follow-up. Quality of life was accessed by the Medical Outcomes Study Short-Form 36 Health Survey. RESULTS: Although SR markedly increased in all patients after GP ablation, the increase was significantly greater in patients <50 years of age than in patients ≥50 years of age (19.3 ± 9.9 beats/min vs. 10.8 ± 5.4 beats/min; p = 0.001). The right anterior GP and the GP at the junction of the aorta and superior vena cava made the greatest contributions to SR increase among all GP. The mean and minimal SR increased significantly after ablation and remained elevated for 12 months only in Group A patients. Although symptoms and quality of life improved in all patients, 5 of the 8 domains of the Medical Outcomes Study Short-Form 36 Health Survey did not show obvious improvements in patients of Group B at 12 months. CONCLUSIONS: Anatomic atrial GP ablation effectively increased SR and improved quality of life in patients <50 years of age with symptomatic SB.

8.
Int J Cardiol ; 211: 7-13, 2016 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-26963618

RESUMO

BACKGROUND: The role of autonomic innervation around the pulmonary vein (PV) antrum in the genesis of atrial fibrillation (AF) has been demonstrated but the characteristics of radiofrequency induced vagal response (VR) in the PV antrum and its clinical impact on pulmonary vein isolation (PVI) for paroxysmal AF need to be further elucidated. METHOD: Of 995 consecutive patients with symptomatic paroxysmal AF undergoing PVI at a single center over a 2-year period, 516 met exclusion criteria and the remaining 479 patients, 156 positive VR (PVR) and 323 negative VR (NVR), underwent 12-month follow-up. The primary endpoint was freedom from AF or other sustained atrial tachycardia (AT), verified by monthly visits and electrocardiographic monitoring. The frequency-domain analysis was performed to evaluate the autonomic activity before and after the procedure. RESULTS: VR was most commonly elicited during PVI at the LSPV roof (65.4%) and anterior RSPV (44.9%, with a >5s sinus pause in 37/70 [52.8%] cases). Compared with the NVR group, ablation was associated with reduced AF recurrence at 12 months in the PVR (hazard ratio: 0.53, 95% confidence interval: 0.22-0.89). Furthermore, the PVR group showed a significantly abbreviated AF cycle length at the left PV, and significantly lower HF and LF parameters with stable LF/HF ratio during follow-up. CONCLUSION: Complete elimination of vagal response, most commonly elicited by radiofrequency application around the roof of LSPV and anterior RSPV, appeared associated with reduced 12-month recurrence of AF and with marked heart rate variability changes consistent with autonomic nervous withdrawal.


Assuntos
Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Ablação por Cateter , Veias Pulmonares/fisiopatologia , Nervo Vago/fisiopatologia , Idoso , Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Veias Pulmonares/inervação , Veias Pulmonares/cirurgia , Nervo Vago/cirurgia
9.
Biochem Biophys Res Commun ; 464(1): 100-5, 2015 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-26056004

RESUMO

AIMS: Atrial fibroblasts and macrophages have long been thought to participate in atrial fibrillation (AF). However, which specific mediator may regulate the interaction between them remains unclear. METHODS AND RESULTS: We provided the evidence for the involvement of Toll/IL-1 receptor domain-containing adaptor inducing IFN-ß (TRIF), an important inflammation-related molecule, in the pathophysiology of AF. Patients with AF showed higher levels of angiotensin II (AngII) and TRIF expression and larger number of macrophages infiltration in left atria appendage than individuals with sinus rhythm (SR). In the cell study, AngII induced chemokines expressions in mouse atrial fibroblasts and AngII-stimulated atrial fibroblasts induced the chemotaxis of macrophages, which were reduced by losartan and TRIF siRNA. Meanwhile, AngII-stimulated atrial fibroblasts proliferation was enhanced by macrophages. CONCLUSIONS: Our data demonstrated that TRIF may be a crucial factor promoting the interaction between atrial fibroblasts and macrophages, leading to atrial fibrosis.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Fibrilação Atrial/metabolismo , Fibroblastos/metabolismo , Átrios do Coração/metabolismo , Macrófagos/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/antagonistas & inibidores , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Fibrilação Atrial/genética , Fibrilação Atrial/patologia , Fibrilação Atrial/cirurgia , Comunicação Celular , Proliferação de Células/efeitos dos fármacos , Quimiotaxia , Fibroblastos/patologia , Fibrose , Regulação da Expressão Gênica , Átrios do Coração/patologia , Átrios do Coração/cirurgia , Humanos , Losartan/farmacologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
10.
Int J Mol Med ; 36(1): 282-8, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25963046

RESUMO

Dilated cardiomyopathy (DCM) represents the most prevalent form of primary cardiomyopathy, and is the most common reason for heart transplantation and a major cause of congestive heart failure. Aggregating evidence demonstrates that genetic defects are associated with DCM, and a great number of mutations in >50 genes have been linked to DCM. However, DCM is a genetically heterogeneous disorder and the genetic components underpinning DCM in a significant proportion of patients remain unknown. In the present study, the coding exons and flanking exon­intron boundaries of the T-Box 5 (TBX5) gene, which encodes a T­box transcription factor required for normal cardiac development, were sequenced in 146 unrelated patients with sporadic DCM. The functional characteristics of the mutant TBX5 were assayed in contrast to its wild­type counterpart by using a dual­luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.A143T, was identified in a patient with sporadic DCM. The missense mutation, which was absent in 400 control chromosomes, altered the amino acid that was completely conserved evolutionarily among species. Biological analyses revealed that the A143T mutation of TBX5 was associated with significantly decreased transcriptional activity on the promoter of the target gene atrial natriuretic factor (ANF), when compared to its wild­type counterpart. Furthermore, the A143T mutation abolished the synergistic activation of the ANF promoter between TBX5 and GATA binding protein 4 (GATA4), another crucial transcriptional factor for heart development. To the best of our knowledge, this is the first report on the association of a TBX5 loss­of­function mutation with an enhanced susceptibility to sporadic DCM, providing novel insight into the molecular mechanisms of the pathogenesis of DCM and suggesting potential implications for the prenatal prophylaxis and personalized treatment of this commonest primary myocardial disease.


Assuntos
Fator Natriurético Atrial/genética , Cardiomiopatia Dilatada/genética , Fator de Transcrição GATA4/genética , Mutação de Sentido Incorreto/genética , Proteínas com Domínio T/genética , Sequência de Aminoácidos , Sequência de Bases , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Regiões Promotoras Genéticas/genética , Alinhamento de Sequência , Análise de Sequência de DNA , Transcrição Genética/genética , Ativação Transcricional/genética
11.
Exp Cell Res ; 330(1): 43-55, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25152439

RESUMO

The exact mechanisms underlying inhibitory effects of pioglitazone (Pio) on Angiotensin II (AngII)-induced atrial fibrosis are complex and remain largely unknown. In the present study, we examined the effect of Pio on AngII-induced mice atrial fibrosis in vivo and atrial fibroblasts proliferation in vitro. In vivo study showed that AngII infusion induced atrial fibrosis and increased expressions of Toll/IL-1 receptor domain-containing adaptor inducing IFN-ß (TRIF) and tumor necrosis factor receptor associated factor 6 (TRAF6) in mice models. However, those effects could be attenuated by Pio (P<0.01). As for in vitro experiment, Pio suppressed AngII-induced atrial fibroblasts proliferation via nuclear factor-κB/transforming growth factor-ß1/TRIF/TRAF6 signaling pathway in primary cultured mice atrial fibroblasts (P<0.01). In conclusion, suppression of Pio on AngII-induced atrial fibrosis might be related to its inhibitory effects on above signaling pathway.


Assuntos
Angiotensina II/farmacologia , Proliferação de Células , Miofibroblastos/metabolismo , Transdução de Sinais , Tiazolidinedionas/farmacologia , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Fibrose/metabolismo , Átrios do Coração/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/fisiologia , NF-kappa B/metabolismo , Pioglitazona , Fator 6 Associado a Receptor de TNF/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
12.
Int J Mol Med ; 34(5): 1315-22, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25119427

RESUMO

Dilated cardiomyopathy (DCM), the most prevalent form of primary heart muscle disease, is the third most common cause of heart failure and the most frequent reason for cardiac transplantation. Mounting evidence has demonstrated that genetic risk factors are crucial in the pathogenesis of DCM. However, DCM is genetically heterogeneous, and the genetic basis of DCM in a large majority of cases remains unclear. In the current study, the coding exons and flanking introns of the GATA6 gene, which encodes a zinc­finger transcription factor essential for cardiogenesis, was sequenced in 140 unrelated patients with DCM, and two novel heterozygous mutations, p.C447Y and p.H475R, were identified in two index patients with DCM, respectively. Analysis of the pedigrees showed that in each family the mutation co-segregated with DCM transmitted in an autosomal-dominant pattern, with complete penetrance. The missense mutations were absent in 400 control chromosomes and predicted to be disease-causing by MutationTaster or probably damaging by PolyPhen-2. The alignment of multiple GATA6 proteins across species revealed that the altered amino acids were completely conserved evolutionarily. The functional assays showed that the mutated GATA6 proteins were associated with significantly reduced transcriptional activation in comparison with their wild-type counterpart. To the best of our knowledge, this is the first study on the association of GATA6 loss-of-function mutations with enhanced susceptibility to familial DCM, which provides novel insight into the molecular mechanism of DCM and suggests potential implications for the antenatal prophylaxis and allele-specific treatment of DCM.


Assuntos
Cardiomiopatia Dilatada/genética , Fator de Transcrição GATA6/genética , Mutação de Sentido Incorreto , Adulto , Idoso , Sequência de Aminoácidos , Éxons , Feminino , Fator de Transcrição GATA6/metabolismo , Predisposição Genética para Doença , Heterozigoto , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Estudos Prospectivos , Alinhamento de Sequência , Análise de Sequência de DNA , Ativação Transcricional
13.
Int J Med Sci ; 11(6): 554-63, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24782644

RESUMO

Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia in humans and is responsible for substantial morbidity and mortality worldwide. Emerging evidence indicates that abnormal cardiovascular development is involved in the pathogenesis of AF. In this study, the coding exons and splice sites of the NKX2-5 gene, which encodes a homeodomain-containing transcription factor essential for cardiovascular genesis, were sequenced in 146 unrelated patients with lone AF as well as the available relatives of the mutation carriers. A total of 700 unrelated ethnically matched healthy individuals used as controls were genotyped. The disease-causing potential of the identified NKX2-5 variations was predicted by MutationTaster and PolyPhen-2. The functional characteristics of the mutant NKX2-5 proteins were analyzed using a dual-luciferase reporter assay system. As a result, two heterozygous NKX2-5 mutations, including a previously reported p.E21Q and a novel p.T180A mutation, were identified in two families with AF transmitted in an autosomal dominant pattern. The mutations co-segregated with AF in the families with complete penetrance. The detected substitutions, which altered the amino acids highly conserved evolutionarily across species, were absent in 700 control individuals and were both predicted to be causative. Functional analyses demonstrated that the NKX2-5 mutants were associated with significantly decreased transcriptional activity compared with their wild-type counterpart. The findings expand the spectrum of NKX2-5 mutations linked to AF and provide additional evidence that dysfunctional NKX2-5 may confer vulnerability to AF, suggesting the potential benefit for the early prophylaxis and personalized treatment of AF.


Assuntos
Fibrilação Atrial/genética , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Medicina de Precisão , Fatores de Transcrição/genética , Adulto , Grupo com Ancestrais do Continente Asiático , Fibrilação Atrial/patologia , Feminino , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/química , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Sítios de Splice de RNA/genética , Alinhamento de Sequência , Relação Estrutura-Atividade , Fatores de Transcrição/química
14.
Eur Heart J ; 35(20): 1327-34, 2014 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-24497338

RESUMO

AIM: Although catheter ablation (CA) has replaced antiarrhythmic drugs (AAD) as first-line treatment in selected patients with atrial fibrillation (AF), optimal treatment of recurrent atrial tachycardia (AT) after AF ablation remains unclear. This parallel randomized controlled study compared CA vs. AAD for recurrent AT after persistent AF ablation. METHODS AND RESULTS: Two-hundred and one patients (aged 59.1 ± 10.9 years, 68.7% male) with recurrent AT after persistent AF ablation were enrolled and randomized to either CA (n = 101) or AAD (n = 100) treatment. Primary endpoint was freedom from recurrent atrial tachyarrhythmia (ATa, including AT and AF) at 24-month follow-up. Composite secondary endpoints comprised procedural complications, long-term morbidity and improvement in quality of life (QoL). On an intention-to-treat basis, the CA group had a higher rate of freedom from recurrent ATa (56.4 vs. 34.0%; P = 0.001). Adjusted Cox regression analysis showed a significant treatment effect with a hazard ratio of 0.538 (95% CI: 0.355-0.816) in favour of CA. There was a higher proportion of periprocedural complications in the CA group (7.9 vs. 0; P = 0.012), and of long-term adverse events in the AAD group (10.9 vs. 24.0%; P = 0.014). Quality of life was significantly higher for CA. CONCLUSIONS: This study demonstrates superiority of CA over AAD for recurrent AT after persistent AF ablation with regard to SR maintenance, long-term safety and QoL improvement. However, CA use might be limited by a higher risk for periprocedural complications.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/mortalidade , Ablação por Cateter/mortalidade , Doença Crônica , Técnicas Eletrofisiológicas Cardíacas/métodos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Recidiva , Prevenção Secundária/métodos , Resultado do Tratamento
15.
Int J Mol Med ; 33(3): 654-60, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24366163

RESUMO

Dilated cardiomyopathy (DCM) is the most common form of primary myocardial disorder and is associated with substantial morbidity and mortality. Increasing evidence suggests that genetic risk factors play an important role in the pathogenesis of idiopathic DCM. However, DCM is a genetically heterogeneous disease, and the genetic defects responsible for DCM in an overwhelming majority of cases remain to be identified. In the present study, the entire coding region and the splice junction sites of the GATA4 gene, which encodes a cardiac transcription factor essential for cardiogenesis, were sequenced in 150 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped. The functional characteristics of the mutant GATA4 were delineated in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 mutation, p.V291L, was identified in a family with DCM inherited in an autosomal dominant pattern, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes, and the altered amino acid was completely conserved evolutionarily among species. Functional analysis revealed that the GATA4 mutant was associated with significantly diminished transcriptional activity. The findings expand the mutational spectrum of GATA4 linked to DCM and provide novel insight into the molecular etiology involved in DCM, suggesting the potential implications in the early prophylaxis and allele-specific treatment for this common type of cardiomyopathy.


Assuntos
Cardiomiopatia Dilatada/genética , Fator de Transcrição GATA4/genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto/genética , Adulto , Idoso , Processamento Alternativo/genética , Cardiomiopatia Dilatada/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Sítios de Splice de RNA/genética , Alinhamento de Sequência
16.
Int J Cardiol ; 169(1): 35-43, 2013 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-24083885

RESUMO

BACKGROUND: The benefits and risks of additional complex fractionated atrial electrograms (CFAE) ablation in patients with atrial fibrillation (AF) remain unclear. METHODS: Trials were identified in PubMed, Embase, Web of Science, and Cochrane Database, reviews, and reference lists of relevant papers. The primary end point was the recurrence of atrial arrhythmias after a single ablation. RESULTS: We meta-analyzed 11 studies (total, n=983) using random-effects model to compare PVI (n=478) with PVI plus CFAE ablation (PVI+CFAE) (n=505). Additional CFAE ablation reduced recurrence of atrial tachyarrhythmia after a single procedure (pooled RR 0.73; 95% CI 0.61, 0.88; P=0.0007) at ≥ 3-month follow-up. There was no evidence of heterogeneity among studies (I(2)=33%). Subgroup analysis demonstrated that additional CFAE ablation reduced rates of recurrence in nonparoxysmal AF (RR 0.68; 95% CI 0.47, 0.99; P=0.05), whereas had no effect on patients with paroxysmal AF (RR 0.79; 95% CI 0.59, 1.06; P=0.12). Eight studies reported results of post-procedure ATs. The addition of CFAE ablation increased the rate of post-procedure ATs (RR 1.77; 95% CI 1.02, 3.07; P=0.04). Additional CFAE ablation significantly increased mean procedural times (245.4+75.7 vs. 189.5+62.3 min, P<0.001), mean fluoroscopy (72.1+25.6 vs. 59.5+19.3 min, P<0.001), and mean RF energy application times (75.3+38.6 vs. 53.2+27.5 min, P<0.001). CONCLUSIONS: The adjunctive CFAE ablation could provide additional benefit in terms of reducing recurrence of atrial tachyarrhythmia for patients with nonparoxysmal AF but not for patients with paroxysmal AF after a single procedure with or without antiarrhythmic drugs (AADs). The main risk of adjunctive CFAE ablation is the increasing rate of untraceable postablation ATs.


Assuntos
Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Técnicas Eletrofisiológicas Cardíacas/métodos , Átrios do Coração/fisiopatologia , Fibrilação Atrial/diagnóstico , Ablação por Cateter/efeitos adversos , Técnicas Eletrofisiológicas Cardíacas/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Medição de Risco , Resultado do Tratamento
17.
Biochem Biophys Res Commun ; 439(4): 591-6, 2013 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-24041700

RESUMO

The cardiac transcription factor GATA4 is essential for cardiac development, and mutations in this gene have been implicated in a wide variety of congenital heart diseases in both animal models and humans. However, whether mutated GATA4 predisposes to dilated cardiomyopathy (DCM) remains unknown. In this study, the whole coding region and splice junction sites of the GATA4 gene was sequenced in 110 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped. The functional effect of the mutant GATA4 was characterized in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 mutation, p.C271S, was identified in a family with DCM inherited as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily among species. Functional analysis demonstrated that the GATA4 mutant was associated with significantly decreased transcriptional activity and remarkably reduced synergistic activation between GATA4 and NKX2-5, another transcription factor crucial for cardiogenesis. The findings provide novel insight into the molecular mechanisms involved in the pathogenesis of DCM, suggesting the potential implications in the prenatal diagnosis and gene-specific treatment for this common form of myocardial disorder.


Assuntos
Cardiomiopatia Dilatada/genética , Fator de Transcrição GATA4/genética , Mutação , Adulto , Feminino , Fator de Transcrição GATA4/metabolismo , Predisposição Genética para Doença , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
18.
Int J Cardiol ; 168(6): 5372-7, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24016546

RESUMO

BACKGROUND: In our previous prospective and randomized study, we have demonstrated that the concomitant surgical ablation using saline-irrigated cooled tip radiofrequency ablation (SICTRA) system is more effective than subsequent circumferential pulmonary vein isolation (CPVI) combined with substrate modification in treating patients with long-standing persistent atrial fibrillation (LS-AF) and rheumatic heart disease (RHD) undergoing cardiac surgery during middle-term follow-up. Whether this strategy also decreases longer-term arrhythmia recurrence is unknown. This study describes the 4-year efficacy of SICTRA for these patients. Furthermore, we seek to compare the electrophysiological characteristics for recurrent atrial tachyarrhythmia (ATa) at the session of catheter ablation between two groups. METHODS: Long-term follow-up was performed in 95 patients who underwent the catheter ablation strategy (n=47, Group A) or SICTRA (n=48, Group B) combined with valvular surgery for symptomatic LS-AF patients with RHD. RESULTS: After one procedure, Group B had a significantly higher freedom from ATa compared with Group A (29/48 vs 15/47, P=0.005) after a mean follow-up of 54 months (range 48 to 63 months). Catheter-based mapping and ablation of recurrent ATa showed larger amounts of macro-reentrant atrial tachycardias (ATs) in Group B and higher incidence of pulmonary vein (PV) recovery in Group A. After multiple catheter ablations for recurrent ATa, sinus rhythm (SR) could be maintained equally between two groups. CONCLUSIONS: Single procedure success seems to be higher with SICTRA but repeated catheter ablation potentially results in comparable outcomes in treating patients with LS-AF and RHD during long-term follow-up. More macro-reentrant ATs and more PV recoveries are identified to be responsible for ATa in SICTRA and catheter ablation group, respectively.


Assuntos
Fibrilação Atrial/cirurgia , Procedimentos Cirúrgicos Cardíacos , Ablação por Cateter , Cardiopatia Reumática/cirurgia , Adulto , Idoso , Fibrilação Atrial/fisiopatologia , Eletrofisiologia Cardíaca , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Veias Pulmonares/cirurgia , Recidiva , Cardiopatia Reumática/fisiopatologia , Esternotomia , Resultado do Tratamento
19.
Chin Med J (Engl) ; 126(14): 2607-12, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23876880

RESUMO

BACKGROUND: Circumferential pulmonary vein isolation (CPVI), as the basal ablation strategy for treating atrial fibrillation (AF), not only isolates the connection between the left atrium (LA) and the pulmonary veins (PVs), but also induces extensive atrial endocardia damage. This could have an effect on the sinus pulse conduction in the LA and subsequently result in changes of P-wave characteristics of surface electrocardiogram (ECG). METHODS: Fifty consecutive patients underwent CPVI for symptomatic drug-refractory paroxysmal AF. The 12-lead ECGs were recorded one day before CPVI and seven days after CPVI at sinus rhythm by a standard resting ECG device. Measured characteristics of the P-wave consisted of P-wave duration (PWD), P-wave amplitude (PWA), P-wave polarity (PWP), P-wave notch, P-wave dispersion and P-wave index. RESULTS: After CPVI, a prevalent decrease of PWD, PWA, and P-wave dispersion was observed; a transition of P-wave polarity was observed in the leads of III, aVL and aVF. The rate of P-wave notch decreased significantly in all leads, especially in the leads of II, III, aVF and V3. Patients with sinus rhythm had a shorter P-wave dispersion and P-wave index and had a lower rate of P-wave notch compared with the patients with recurrent atrial tachyarrhythmia. CONCLUSION: Observations from using the surface ECG showed that CPVI has instant effects on the electrical conduction in the LA, and several changes of P-wave characteristics associated with development of AF are improved by CPVI.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Eletrocardiografia , Veias Pulmonares/cirurgia , Idoso , Fibrilação Atrial/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade
20.
Pacing Clin Electrophysiol ; 36(10): 1236-44, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23822135

RESUMO

OBJECTIVES: It is uncertain whether gender affects the outcomes of catheter ablation (CA) for atrial fibrillation (AF). The objective of the study is to evaluate the efficacy and safety of CA for long-standing persistent AF in women. METHODS: Between January 2010 and May 2011, 220 consecutive patients (73 females, 33.2%), with long-standing persistent AF who underwent CA were prospectively recruited. Gender-related differences in clinical presentation, periprocedural complications, and outcomes were compared. RESULTS: Women were less likely to have lone AF than men (27.4% vs 47.6%; P = 0.004). The incidence of rheumatic heart disease was higher in women (19.2% in women vs 1.4% in men; P < 0.001). Women had a lower initial ablation success rate than men (35.6% vs 57.1%; P = 0.003). Hematomas occurred more often in women (6.8% in women vs 0.7% in men; P = 0.027). A Cox regression analysis demonstrated total duration of AF (per month, hazard ratio [HR] 1.003, confidence interval [CI] 1.001-1.006; P = 0.006) and gender (HR 1.663, CI 1.114-2.485; P = 0.013) as the independent predictors for recurrence after the first CA. CONCLUSIONS: Women and long AF duration were closely related to the recurrence of AF after the first ablation in patients with long-standing persistent AF. Women also had a higher risk of vascular complications.


Assuntos
Fibrilação Atrial/mortalidade , Fibrilação Atrial/cirurgia , Ablação por Cateter/mortalidade , Complicações Pós-Operatórias/mortalidade , Saúde da Mulher/estatística & dados numéricos , China/epidemiologia , Doença Crônica , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Distribuição por Sexo , Taxa de Sobrevida , Resultado do Tratamento
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